Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio Finland

International Clinical Research Center St Anne University Hospital Brno Czechia

Loschmidt Laboratories Department of Experimental Biology and RECETOX Faculty of Science Masaryk University Brno Czechia

School of Pharmacy Faculty of Health Sciences University of Eastern Finland Kuopio Finland

University Hospital Tübingen Department of Internal Medicine 8 University of Tübingen Tübingen Germany

Zobrazit více v PubMed

Abdelrahim M., Matsuda A., Naing A. (2013). TAS-106: preclinical, clinical and beyond. Oncology 85, 356–363. 10.1159/000356571 PubMed DOI

Alqahtani A., Choucair K., Ashraf M., Hammouda D. M., Alloghbi A., Khan T., et al. . (2019). Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. Future Sci. 5:115. 10.4155/fsoa-2018-0115 PubMed DOI PMC

Arkin M. R., Tang Y., Wells J. A. (2014). Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol. 21, 1102–1114. 10.1016/j.chembiol.2014.09.001 PubMed DOI PMC

Arruebo M., Vilaboa N., Sáez-Gutierrez B., Lambea J., Tres A., Valladares M., et al. . (2011). Assessment of the evolution of cancer treatment therapies. Cancers 3, 3279–3330. 10.3390/cancers3033279 PubMed DOI PMC

Asghar U., Witkiewicz A. K., Turner N. C., Knudsen E. S. (2015). The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug. Discov. 14, 130–146. 10.1038/nrd4504 PubMed DOI PMC

Babokhov M., Hibino K., Itoh Y., Maeshima K. (2020). Local chromatin motion and transcription. J. Mol. Biol. 432, 694–700. 10.1016/j.jmb.2019.10.018 PubMed DOI

Balakrishnan K., Stellrecht C. M., Genini D., Ayres M., Wierda W. G., Keating M. J., et al. . (2005). Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP. Blood 105, 4455–4462. 10.1182/blood-2004-05-1699 PubMed DOI PMC

Ballou L. M., Lin R. Z. (2008). Rapamycin and mTOR kinase inhibitors. J. Chem. Biol. 1, 27–36. 10.1007/s12154-008-0003-5 PubMed DOI PMC

Banerjee S., Saluja A. (2015). Minnelide, a novel drug for pancreatic and liver cancer. Pancreatology 15, S39–S43. 10.1016/j.pan.2015.05.472 PubMed DOI PMC

Bartsch R. (2017). Ribociclib: a valuable addition to treatment options in breast cancer? ESMO Open 2:246. 10.1136/esmoopen-2017-000246 PubMed DOI PMC

Beg M. S., Brenner A. J., Sachdev J., Borad M., Kang Y.-K., Stoudemire J., et al. . (2017). Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest New Drugs 35, 180–188. 10.1007/s10637-016-0407-y PubMed DOI PMC

Bhat M., Robichaud N., Hulea L., Sonenberg N., Pelletier J., Topisirovic I. (2015). Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 14, 261–278. 10.1038/nrd4505 PubMed DOI

Bhullar K. S., Lagarón N. O., McGowan E. M., Parmar I., Jha A., Hubbard B. P., et al. . (2018). Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer 17:48. 10.1186/s12943-018-0804-2 PubMed DOI PMC

Blachly J. S., Byrd J. C. (2013). Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk. Lymphoma 54, 2133–2143. 10.3109/10428194.2013.783911 PubMed DOI PMC

Blum K. A., Ruppert A. S., Woyach J. A., Jones J. A., Andritsos L., Flynn J. M., et al. . (2011). Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. Leukemia 25, 1444–1451. 10.1038/leu.2011.109 PubMed DOI PMC

Bogdahn U., Hau P., Stockhammer G., Venkataramana N. K., Mahapatra A. K., Suri A., et al. . (2011). Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 13, 132–142. 10.1093/neuonc/noq142 PubMed DOI PMC

Bolden J. E., Tasdemir N., Dow L. E., van Es J. H., Wilkinson J. E., Zhao Z., et al. . (2014). Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell Rep. 8, 1919–1929. 10.1016/j.celrep.2014.08.025 PubMed DOI PMC

Bordeleau M.-E., Robert F., Gerard B., Lindqvist L., Chen S. M. H., Wendel H.-G., et al. . (2008). Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J. Clin. Invest. 118, 2651–2660. 10.1172/JCI34753 PubMed DOI PMC

Bouras E., Karakioulaki M., Bougioukas K. I., Aivaliotis M., Tzimagiorgis G., Chourdakis M. (2019). Gene promoter methylation and cancer: an umbrella review. Gene 710, 333–340. 10.1016/j.gene.2019.06.023 PubMed DOI

Brian P. W., Curtis P. J., Hemming H. G., Norris G. L. F. (1957). Wortmannin, an antibiotic produced by Penicillium wortmanni. Trans. Br. Mycol. Soc. 40:365 10.1016/S0007-1536(57)80033-3 DOI

Buettner R., Nguyen L. X. T., Kumar B., Morales C., Liu C., Chen L. S., et al. . (2019). 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia. J. Cell. Physiol. 10.1002/jcp.28294. [Epub ahead of print]. PubMed DOI PMC

Bushweller J. H. (2019). Targeting transcription factors in cancer — from undruggable to reality. Nat. Rev. Cancer 19, 611–624. 10.1038/s41568-019-0196-7 PubMed DOI PMC

Byrd J. C., Lin T. S., Dalton J. T., Wu D., Phelps M. A., Fischer B., et al. . (2007). Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109, 399–404. 10.1182/blood-2006-05-020735 PubMed DOI PMC

Bywater M. J., Poortinga G., Sanij E., Hein N., Peck A., Cullinane C., et al. . (2012). Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22, 51–65. 10.1016/j.ccr.2012.05.019 PubMed DOI PMC

Canon J., Rex K., Saiki A. Y., Mohr C., Cooke K., Bagal D., et al. . (2019). The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223. 10.1038/s41586-019-1694-1 PubMed DOI

Castel S. E., Martienssen R. A. (2013). RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet. 14, 100–112. 10.1038/nrg3355 PubMed DOI PMC

Cencic R., Carrier M., Galicia-Vázquez G., Bordeleau M.-E., Sukarieh R., Bourdeau A., et al. . (2009). Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS ONE 4:e5223. 10.1371/journal.pone.0005223 PubMed DOI PMC

Chen P., Lee N. V., Hu W., Xu M., Ferre R. A., Lam H., et al. . (2016a). Spectrum and degree of CDK drug interactions predicts clinical performance. Mol. Cancer Ther. 15, 2273–2281. 10.1158/1535-7163.MCT-16-0300 PubMed DOI

Chen Q.-X., Wang W.-P., Zeng S., Urayama S., Yu A.-M. (2015). A general approach to high-yield biosynthesis of chimeric RNAs bearing various types of functional small RNAs for broad applications. Nucleic Acids Res 43, 3857–3869. 10.1093/nar/gkv228 PubMed DOI PMC

Chen W.-L., Pan L., Kinghorn A. D., Swanson S. M., Burdette J. E. (2016b). Silvestrol induces early autophagy and apoptosis in human melanoma cells. BMC Cancer 16:17. 10.1186/s12885-015-1988-0 PubMed DOI PMC

Cheng Y., He C., Wang M., Ma X., Mo F., Yang S., et al. . (2019). Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Trans. Targeted Therap. 4, 1–39. 10.1038/s41392-019-0095-0 PubMed DOI PMC

Chery J. (2016). RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc J. 4, 35–50. 10.14304/surya.jpr.v4n7.5 PubMed DOI PMC

Choo A. Y., Yoon S.-O., Kim S. G., Roux P. P., Blenis J. (2008). Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl. Acad. Sci. U.S.A. 105, 17414–17419. 10.1073/pnas.0809136105 PubMed DOI PMC

Chung J., Kuo C. J., Crabtree G. R., Blenis J. (1992). Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227–1236. 10.1016/0092-8674(92)90643-q PubMed DOI

Cochet-Meilhac M., Chambon P. (1974). Animal DNA-dependent RNA polymerases 11. Mechanism of the inhibition of RNA polymerases B by amatoxins. Biochim. Biophys. Acta 353, 160–184. 10.1016/0005-2787(74)90182-8 PubMed DOI

Colis L., Peltonen K., Sirajuddin P., Liu H., Sanders S., Ernst G., et al. . (2014). DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response. Oncotarget 5, 4361–4369. 10.18632/oncotarget.2020 PubMed DOI PMC

Cortes J., Digumarti R., Parikh P. M., Wetzler M., Lipton J. H., Hochhaus A., et al. . (2013). Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am. J. Hematol. 88, 350–354. 10.1002/ajh.23408 PubMed DOI PMC

Cortes J., Lipton J. H., Rea D., Digumarti R., Chuah C., Nanda N., et al. . (2012). Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120, 2573–2580. 10.1182/blood-2012-03-415307 PubMed DOI PMC

Cramer P. (2004). Structure and Function of RNA Polymerase II, in Advances in Protein Chemistry Proteins in Eukaryotic Transcription (New York, NY: John Wiley & Sons; ), 1–42. 10.1016/S0065-3233(04)67001-X PubMed DOI

Cramer P. (2019). Eukaryotic transcription turns 50. Cell 179, 808–812. 10.1016/j.cell.2019.09.018 PubMed DOI

Croce C. M. (2008). Oncogenes and cancer. N. Engl. J. Med. 358, 502–511. 10.1056/NEJMra072367 PubMed DOI

Crooke S. T. (2017). Molecular mechanisms of antisense oligonucleotides. Nucleic Acid Therap. 27, 70–77. 10.1089/nat.2016.0656 PubMed DOI PMC

Darnell J. E. (2002). Transcription factors as targets for cancer therapy. Nat. Rev. Cancer 2, 740–749. 10.1038/nrc906 PubMed DOI

de la Cruz A., Vera-Zambrano A., Peraza D. A., Valenzuela C., Zapata J. M., Perez-Chacon G., et al. . (2017). Fludarabine Inhibits KV1.3 Currents in Human B Lymphocytes. Front. Pharmacol. 8:177. 10.3389/fphar.2017.00177 PubMed DOI PMC

Dean J. L., Thangavel C., McClendon A. K., Reed C. A., Knudsen E. S. (2010). Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29, 4018–4032. 10.1038/onc.2010.154 PubMed DOI

Dennison J. B., Shanmugam M., Ayres M. L., Qian J., Krett N. L., Medeiros L. J., et al. . (2010). 8-Aminoadenosine inhibits Akt/mTOR and Erk signaling in mantle cell lymphoma. Blood 116, 5622–5630. 10.1182/blood-2010-05-285866 PubMed DOI PMC

Ding Q., Zhang Z., Liu J.-J., Jiang N., Zhang J., Ross T. M., et al. . (2013). Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J. Med. Chem. 56, 5979–5983. 10.1021/jm400487c PubMed DOI

Dowdy S. F. (2017). Overcoming cellular barriers for RNA therapeutics. Nat. Biotechnol. 35, 222–229. 10.1038/nbt.3802 PubMed DOI

Drygin D., Lin A., Bliesath J., Ho C. B., O'Brien S. E., Proffitt C., et al. . (2011). Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 71, 1418–1430. 10.1158/0008-5472.CAN-10-1728 PubMed DOI

Duan Z., Yu A.-M. (2016). Bioengineered non-coding RNA agent (BERA) in action. Bioengineered 7, 411–417. 10.1080/21655979.2016.1207011 PubMed DOI PMC

Duman-Scheel M. (2019). Saccharomyces cerevisiae (Baker's Yeast) as an interfering RNA expression and delivery system. Curr. Drug Targets 20, 942–952. 10.2174/1389450120666181126123538 PubMed DOI PMC

Ettl J. (2019). Management of adverse events due to cyclin-dependent kinase 4/6 inhibitors. BRC 14, 86–92. 10.1159/000499534 PubMed DOI PMC

Faller W. J., Jackson T. J., Knight J. R. P., Ridgway R. A., Jamieson T., Karim S. A., et al. . (2015). mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517, 497–500. 10.1038/nature13896 PubMed DOI PMC

Fan Q., Aksoy O., Wong R. A., Ilkhanizadeh S., Novotny C. J., Gustafson W. C., et al. . (2017). A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. Cancer Cell 31, 424–435. 10.1016/j.ccell.2017.01.014 PubMed DOI PMC

Fan Q.-W., Knight Z. A., Goldenberg D. D., Yu W., Mostov K. E., Stokoe D., et al. . (2006). A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9, 341–349. 10.1016/j.ccr.2006.03.029 PubMed DOI PMC

Feldman M. E., Apsel B., Uotila A., Loewith R., Knight Z. A., Ruggero D., et al. . (2009). Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7:e38. 10.1371/journal.pbio.1000038 PubMed DOI PMC

Filippakopoulos P., Qi J., Picaud S., Shen Y., Smith W. B., Fedorov O., et al. . (2010). Selective inhibition of BET bromodomains. Nature 468, 1067–1073. 10.1038/nature09504 PubMed DOI PMC

Finn R. S., Dering J., Conklin D., Kalous O., Cohen D. J., Desai A. J., et al. . (2009). PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11:R77. 10.1186/bcr2419 PubMed DOI PMC

Finn R. S., Martin M., Rugo H. S., Jones S., Im S.-A., Gelmon K., et al. . (2016). Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925–1936. 10.1056/NEJMoa1607303 PubMed DOI

Fire A., Xu S., Montgomery M. K., Kostas S. A., Driver S. E., Mello C. C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811. 10.1038/35888 PubMed DOI

Flaherty K. T. (2006). Chemotherapy and targeted therapy combinations in advanced melanoma. Clin. Cancer Res. 12, 2366–2370. 10.1158/1078-0432.CCR-05-2505 PubMed DOI

Ford B., Boykevisch S., Zhao C., Kunzelmann S., Bar-Sagi D., Herrmann C., et al. . (2009). Characterization of a ras mutant with identical GDP- and GTP-bound structures,. Biochemistry 48, 11449–11457. 10.1021/bi901479b PubMed DOI PMC

Forero-Torres A., Rosen S., Smith D. C., Lesser G., Peguero J., Gupta S., et al. (2017). Preliminary results from an ongoing phase 1/2 Study of INCB057643, a Bromodomain and Extraterminal (BET) Protein Inhibitor, in Patients (pts) with advanced malignancies. Blood 130, 4048–4048. 10.1182/blood.V130.Suppl_1.4048.4048 DOI

Frankowski K. J., Wang C., Patnaik S., Schoenen F. J., Southall N., Li D., et al. . (2018). Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis. Sci. Transl. Med. 10:eaap8307. 10.1126/scitranslmed.aap8307 PubMed DOI PMC

Fresno M., Jiménez A., Vázquez D. (1977). Inhibition of translation in eukaryotic systems by harringtonine. Eur. J. Biochem. 72, 323–330. 10.1111/j.1432-1033.1977.tb11256.x PubMed DOI

Frey J. A., Gandhi V. (2010). 8-Amino-adenosine inhibits multiple mechanisms of transcription. Mol. Cancer Ther. 9, 236–245. 10.1158/1535-7163.MCT-09-0767 PubMed DOI PMC

Friday B., Lassere Y., Meyers C. A., Mita A., Abbruzzese J. L., Thomas M. B. (2012). A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors. Anticancer Res. 32, 1689–1696. Available online at: http://ar.iiarjournals.org/content/32/5/1689.long PubMed

Fu L., Tian M., Li X., Li J., Huang J., Ouyang L., et al. . (2015). Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget 6, 5501–5516. 10.18632/oncotarget.3551 PubMed DOI PMC

Fujisawa T., Filippakopoulos P. (2017). Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 18, 246–262. 10.1038/nrm.2016.143 PubMed DOI

Furet P., Masuya K., Kallen J., Stachyra-Valat T., Ruetz S., Guagnano V., et al. . (2016). Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg. Med. Chem. Lett. 26, 4837–4841. 10.1016/j.bmcl.2016.08.010 PubMed DOI

Galons H., Oumata N., Gloulou O., Meijer L. (2013). Cyclin-dependent kinase inhibitors closer to market launch? Expert Opin. Ther. Pat. 23, 945–963. 10.1517/13543776.2013.789861 PubMed DOI

Gandhi V., Ayres M., Halgren R. G., Krett N. L., Newman R. A., Rosen S. T. (2001). 8-chloro-cAMP and 8-chloro-adenosine act by the same mechanism in multiple myeloma cells. Cancer Res. 61, 5474–5479. Available online at: https://cancerres.aacrjournals.org/content/61/14/5474.long PubMed

Gandhi V., Plunkett W. (2002). Cellular and clinical pharmacology of fludarabine. Clin. Pharmacokinet. 41, 93–103. 10.2165/00003088-200241020-00002 PubMed DOI

Gandhi V., Plunkett W., Cortes J. E. (2014). Omacetaxine: a protein translation inhibitor for treatment of chronic myelogenous leukemia. Clin. Cancer Res. 20, 1735–1740. 10.1158/1078-0432.CCR-13-1283 PubMed DOI PMC

Gavai A. V., Norris D., Tortolani D., O'Malley D., Zhao Y., Quesnelle C., et al. (2018). Abstract 5789: discovery of clinical candidate BMS-986158, an oral BET inhibitor, for the treatment of cancer. Cancer Res. 78, 5789–5789. 10.1158/1538-7445.AM2018-5789 DOI

Golan T., Khvalevsky E. Z., Hubert A., Gabai R. M., Hen N., Segal A., et al. . (2015). RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 6, 24560–24570. 10.18632/oncotarget.4183 PubMed DOI PMC

Goyal N., Narayanaswami P. (2018). Making sense of antisense oligonucleotides: a narrative review. Muscle Nerve 57, 356–370. 10.1002/mus.26001 PubMed DOI

Grabiner B. C., Nardi V., Birsoy K., Possemato R., Shen K., Sinha S., et al. . (2014). A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4, 554–563. 10.1158/2159-8290.CD-13-0929 PubMed DOI PMC

Graham L., Banda K., Torres A., Carver B. S., Chen Y., Pisano K., et al. . (2018). A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer. Invest New Drugs 36, 458–467. 10.1007/s10637-018-0578-9 PubMed DOI PMC

Guichard S. M., Curwen J., Bihani T., D'Cruz C. M., Yates J. W. T., Grondine M., et al. . (2015). AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol. Cancer Ther. 14, 2508–2518. 10.1158/1535-7163.MCT-15-0365 PubMed DOI

Gupta S. V., Sass E. J., Davis M. E., Edwards R. B., Lozanski G., Heerema N. A., et al. . (2011). Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells. AAPS J. 13. 10.1208/s12248-011-9276-7 PubMed DOI PMC

Gürel G., Blaha G., Moore P. B., Steitz T. A. (2009). U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J. Mol. Biol. 389, 146–156. 10.1016/j.jmb.2009.04.005 PubMed DOI PMC

Ha M., Kim V. N. (2014). Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524. 10.1038/nrm3838 PubMed DOI

Haddach M., Schwaebe M. K., Michaux J., Nagasawa J., O'Brien S. E., Whitten J. P., et al. . (2012). Discovery of CX-5461, the first direct and selective inhibitor of RNA polymerase I, for cancer therapeutics. ACS Med. Chem. Lett. 3, 602–606. 10.1021/ml300110s PubMed DOI PMC

Hallin J., Engstrom L. D., Hargis L., Calinisan A., Aranda R., Briere D. M., et al. . (2020). The KRASG12C inhibitor MRTX849 Provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71. 10.1158/2159-8290.CD-19-1167 PubMed DOI PMC

Hammond-Thelin L. A., Thomas M. B., Iwasaki M., Abbruzzese J. L., Lassere Y., Meyers C. A., et al. . (2012). Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies. Invest. New Drugs 30, 316–326. 10.1007/s10637-010-9535-y PubMed DOI

Hanna J., Hossain G. S., Kocerha J. (2019). The potential for microRNA therapeutics and clinical research. Front. Genet. 10:478. 10.3389/fgene.2019.00478 PubMed DOI PMC

Harigaya Y., Parker R. (2010). No-go decay: a quality control mechanism for RNA in translation. WIREs RNA 1, 132–141. 10.1002/wrna.17 PubMed DOI

Havens M. A., Hastings M. L. (2016). Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 44, 6549–6563. 10.1093/nar/gkw533 PubMed DOI PMC

Ho P. Y., Duan Z., Batra N., Jilek J. L., Tu M.-J., Qiu J.-X., et al. . (2018). Bioengineered noncoding RNAs selectively change cellular miRNome profiles for cancer therapy. J. Pharmacol. Exp. Ther. 365, 494–506. 10.1124/jpet.118.247775 PubMed DOI PMC

Holzer S., Rzechorzek N. J., Short I. R., Jenkyn-Bedford M., Pellegrini L., Kilkenny M. L. (2019). Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues fludarabine and vidarabine. ACS Chem. Biol. 14, 1904–1912. 10.1021/acschembio.9b00367 PubMed DOI PMC

Hortobagyi G. N., Stemmer S. M., Burris H. A., Yap Y.-S., Sonke G. S., Paluch-Shimon S., et al. . (2016). Ribociclib as first-line therapy for HR-positive, advanced breast cancer. 375, 1738–1748. 10.1056/NEJMoa1609709 PubMed DOI

Hsieh A. C., Liu Y., Edlind M. P., Ingolia N. T., Janes M. R., Sher A., et al. . (2012). The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61. 10.1038/nature10912 PubMed DOI PMC

Hu S., Marineau J. J., Rajagopal N., Hamman K. B., Choi Y. J., Schmidt D. R., et al. . (2019). Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7. Cancer Res. 79, 3479–3491. 10.1158/0008-5472.CAN-19-0119 PubMed DOI

Hua H., Kong Q., Zhang H., Wang J., Luo T., Jiang Y. (2019). Targeting mTOR for cancer therapy. J. Hematol. Oncol. 12:71. 10.1186/s13045-019-0754-1 PubMed DOI PMC

Huang L., Jin J., Deighan P., Kiner E., McReynolds L., Lieberman J. (2013). Efficient and specific gene knockdown by small interfering RNAs produced in bacteria. Nat. Biotechnol. 31, 350–356. 10.1038/nbt.2537 PubMed DOI PMC

Huang M. T. (1975). Harringtonine, an inhibitor of initiation of protein biosynthesis. Mol. Pharmacol. 11, 511–519. PubMed

Huang P., Sandoval A., Van Den Neste E., Keating M. J., Plunkett W. (2000). Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine. Leukemia 14, 1405–1413. 10.1038/sj.leu.2401845 PubMed DOI

Hwang B. Y., Su B.-N., Chai H., Mi Q., Kardono L. B. S., Afriastini J. J., et al. . (2004). Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris. J. Org. Chem. 69, 3350–3358. 10.1021/jo040120f PubMed DOI

Iadevaia V., Wang X., Yao Z., Foster L. J., Proud C. G. (2012). Evaluation of mTOR-regulated mRNA translation. Methods Mol. Biol. 821, 171–185. 10.1007/978-1-61779-430-8_10 PubMed DOI

Ieguchi K., Maru Y. (2019). Roles of EphA1/A2 and ephrin-A1 in cancer. Cancer Sci. 110, 841–848. 10.1111/cas.13942 PubMed DOI PMC

Janes M. R., Zhang J., Li L.-S., Hansen R., Peters U., Guo X., et al. . (2018). Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589.e17. 10.1016/j.cell.2018.01.006 PubMed DOI

Jian C., Tu M.-J., Ho P. Y., Duan Z., Zhang Q., Qiu J.-X., et al. . (2017). Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models. Oncotarget 8, 30742–30755. 10.18632/oncotarget.16372 PubMed DOI PMC

Jilek J. L., Zhang Q.-Y., Tu M.-J., Ho P. Y., Duan Z., Qiu J.-X., et al. . (2019). Bioengineered Let-7c inhibits orthotopic hepatocellular carcinoma and improves overall survival with minimal immunogenicity. Mol. Therap. Nucleic Acids 14, 498–508. 10.1016/j.omtn.2019.01.007 PubMed DOI PMC

Jinek M., Doudna J. A. (2009). A three-dimensional view of the molecular machinery of RNA interference. Nature 457, 405–412. 10.1038/nature07755 PubMed DOI

John J., Rensland H., Schlichting I., Vetter I., Borasio G. D., Goody R. S., et al. . (1993). Kinetic and structural analysis of the Mg(2+)-binding site of the guanine nucleotide-binding protein p21H-ras. J. Biol. Chem. 268, 923–929. PubMed

Johnson C. E., Tee A. R. (2017). Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. Essays Biochem. 61, 699–710. 10.1042/EBC20170056 PubMed DOI

Juliano R. L. (2016). The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 44, 6518–6548. 10.1093/nar/gkw236 PubMed DOI PMC

Junwei S., Vakoc C. R. (2014). The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell 54, 728–736. 10.1016/j.molcel.2014.05.016 PubMed DOI PMC

Kang S. A., Pacold M. E., Cervantes C. L., Lim D., Lou H. J., Ottina K., et al. . (2013). mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341:1236566. 10.1126/science.1236566 PubMed DOI PMC

Karaki S., Paris C., Rocchi P. (2019). Antisense oligonucleotides, A novel developing targeting therapy. Antisense Therapy. 10.5772/intechopen.82105 DOI

Kaur G., Cheung H.-C., Xu W., Wong J. V., Chan F. F., Li Y., et al. . (2018). Milligram scale production of potent recombinant small interfering RNAs in Escherichia coli. Biotechnol. Bioeng. 115, 2280–2291. 10.1002/bit.26740 PubMed DOI

Kelland L. R. (2000). Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. Expert Opin. Investig. Drugs 9, 2903–2911. 10.1517/13543784.9.12.2903 PubMed DOI

Kharenko O. A., Gesner E. M., Patel R. G., Norek K., White A., Fontano E., et al. . (2016). RVX-297- a novel BD2 selective inhibitor of BET bromodomains. Biochem. Biophys. Res. Commun. 477, 62–67. 10.1016/j.bbrc.2016.06.021 PubMed DOI

Khot A., Brajanovski N., Cameron D. P., Hein N., Maclachlan K. H., Sanij E., et al. . (2019). First-in-Human RNA polymerase I transcription inhibitor CX-5461 in patients with advanced hematologic cancers: results of a phase I dose-escalation study. Cancer Discov. 9, 1036–1049. 10.1158/2159-8290.CD-18-1455 PubMed DOI

Khvalevsky E. Z., Gabai R., Rachmut I. H., Horwitz E., Brunschwig Z., Orbach A., et al. (2013). Mutant KRAS is a druggable target for pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. 110, 20723–20728. 10.1073/pnas.1314307110 PubMed DOI PMC

Khvorova A., Watts J. K. (2017). The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol. 35, 238–248. 10.1038/nbt.3765 PubMed DOI PMC

Kim H. J., Kim A., Miyata K., Kataoka K. (2016). Recent progress in development of siRNA delivery vehicles for cancer therapy. Adv. Drug Deliv. Rev. 104, 61–77. 10.1016/j.addr.2016.06.011 PubMed DOI

Kim J., Guan K.-L. (2019). mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 21, 63–71. 10.1038/s41556-018-0205-1 PubMed DOI

Kjellman C., Olofsson S. P., Hansson O., Schantz T. V., Lindvall M., Nilsson I., et al. . (2000). Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma. Int. J. Cancer 89, 251–258. 10.1002/1097-0215(20000520)89:3<251::AID-IJC7>3.0.CO;2-5 PubMed DOI

Kleinman M. E., Yamada K., Takeda A., Chandrasekaran V., Nozaki M., Baffi J. Z., et al. . (2008). Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597. 10.1038/nature06765 PubMed DOI PMC

Kogure T., Kinghorn A. D., Yan I., Bolon B., Lucas D. M., Grever M. R., et al. . (2013). Therapeutic potential of the translation inhibitor silvestrol in hepatocellular cancer. PLoS ONE 8:e76136. 10.1371/journal.pone.0076136 PubMed DOI PMC

Kornberg R. D. (2005). Mediator and the mechanism of transcriptional activation. Trends Biochem. Sci. 30, 235–239. 10.1016/j.tibs.2005.03.011 PubMed DOI

Koul D., Wang S., Wu S., Saito N., Zheng S., Gao F., et al. . (2017). Preclinical therapeutic efficacy of a novel blood-brain barrier-penetrant dual PI3K/mTOR inhibitor with preferential response in PI3K/PTEN mutant glioma. Oncotarget 8, 21741–21753. 10.18632/oncotarget.15566 PubMed DOI PMC

Kristensen A. R., Gsponer J., Foster L. J. (2013). Protein synthesis rate is the predominant regulator of protein expression during differentiation. Mol. Syst. Biol. 9:689. 10.1038/msb.2013.47 PubMed DOI PMC

Kujirai T., Kurumizaka H. (2019). Transcription through the nucleosome. Curr. Opin. Struct. Biol. 61, 42–49. 10.1016/j.sbi.2019.10.007 PubMed DOI

Kuo C. J., Chung J., Fiorentino D. F., Flanagan W. M., Blenis J., Crabtree G. R. (1992). Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358, 70–73. 10.1038/358070a0 PubMed DOI

Laham-Karam N., Laitinen P., Turunen T. A., Ylä-Herttuala S. (2018). Activating the chromatin by noncoding RNAs. Antioxid. Redox Signal. 29, 813–831. 10.1089/ars.2017.7248 PubMed DOI

Lai F., Damle S. S., Ling K. K., Rigo F. (2020). Directed RNase H cleavage of nascent transcripts causes transcription termination. Mol. Cell. 77, 1032–1043.e4 10.1016/j.molcel.2019.12.029 PubMed DOI

Laikova K. V., Oberemok V. V., Krasnodubets A. M., Gal'chinsky N. V., Useinov R. Z., Novikov I. A., et al. . (2019). Advances in the understanding of skin cancer: ultraviolet radiation, mutations, and antisense oligonucleotides as anticancer drugs. Molecules 24:1516. 10.3390/molecules24081516 PubMed DOI PMC

Landen C. N., Chavez-Reyes A., Bucana C., Schmandt R., Deavers M. T., Lopez-Berestein G., et al. . (2005). Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 65, 6910–6918. 10.1158/0008-5472.CAN-05-0530 PubMed DOI

Lee J.-S., Mendell J. T. (2020). Antisense-mediated transcript knockdown triggers premature transcription termination. Mol. Cell. 77, 1044–1054.e3. 10.1016/j.molcel.2019.12.011 PubMed DOI PMC

Letson C., Padron E. (2019). Non-canonical transcriptional consequences of BET inhibition in cancer. Pharmacol. Res. 150:104508. 10.1016/j.phrs.2019.104508 PubMed DOI

Li C. H., Chen Y. (2013). Targeting long non-coding RNAs in cancers: progress and prospects. Int. J. Biochem. Cell Biol. 45, 1895–1910. 10.1016/j.biocel.2013.05.030 PubMed DOI

Li J., Kim S. G., Blenis J. (2014). Rapamycin: one drug, many effects. Cell Metab. 19, 373–379. 10.1016/j.cmet.2014.01.001 PubMed DOI PMC

Li M.-M., Addepalli B., Tu M.-J., Chen Q.-X., Wang W.-P., Limbach P. A., et al. . (2015). Chimeric MicroRNA-1291 biosynthesized efficiently in Escherichia coli is effective to reduce target gene expression in human carcinoma cells and improve chemosensitivity. Drug Metab. Dispos. 43, 1129–1136. 10.1124/dmd.115.064493 PubMed DOI PMC

Liang X., Nichols J. G., Hsu C.-W., Vickers T. A., Crooke S. T. (2019a). mRNA levels can be reduced by antisense oligonucleotides via no-go decay pathway. Nucleic Acids Res. 47, 6900–6916. 10.1093/nar/gkz500 PubMed DOI PMC

Liang X., Xie R., Su J., Ye B., Wei S., Liang Z., et al. . (2019b). Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis. J. Exp. Clin. Cancer Res. 38:217. 10.1186/s13046-019-1232-x PubMed DOI PMC

Lindell T. J., Weinberg F., Morris P. W., Roeder R. G., Rutter W. J. (1970). Specific inhibition of nuclear RNA polymerase II by alpha-amanitin. Science 170, 447–449. 10.1126/science.170.3956.447 PubMed DOI

Lindsay C. R., Blackhall F. H. (2019). Direct Ras G12C inhibitors: crossing the rubicon. Br. J Cancer 121, 197–198. 10.1038/s41416-019-0499-1 PubMed DOI PMC

Linnane E., Davey P., Zhang P., Puri S., Edbrooke M., Chiarparin E., et al. . (2019). Differential uptake, kinetics and mechanisms of intracellular trafficking of next-generation antisense oligonucleotides across human cancer cell lines. Nucleic Acids Res. 47, 4375–4392. 10.1093/nar/gkz214 PubMed DOI PMC

Liu Q., Xu C., Kirubakaran S., Zhang X., Hur W., Liu Y., et al. . (2013). Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res. 73, 2574–2586. 10.1158/0008-5472.CAN-12-1702 PubMed DOI PMC

Logan K., Zhang J., Davis E. A., Ackerman S. (1989). Drug Inhibitors of RNA Polymerase II Transcription. DNA 8, 595–604. 10.1089/dna.1989.8.595 PubMed DOI

Lu J. (2015). Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer. J. Hematol. Oncol. 8:98. 10.1186/s13045-015-0194-5 PubMed DOI PMC

Lucas D. M., Edwards R. B., Lozanski G., West D. A., Shin J. D., Vargo M. A., et al. . (2009). The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood 113, 4656–4666. 10.1182/blood-2008-09-175430 PubMed DOI PMC

Lv H., Zhang S., Wang B., Cui S., Yan J. (2006). Toxicity of cationic lipids and cationic polymers in gene delivery. J. Control. Release 114, 100–109. 10.1016/j.jconrel.2006.04.014 PubMed DOI

Lykke-Andersen S., Jensen T. H. (2007). Overlapping pathways dictate termination of RNA polymerase II transcription. Biochimie 89, 1177–1182. 10.1016/j.biochi.2007.05.007 PubMed DOI

MacLeod A. R., Crooke S. T. (2017). RNA therapeutics in oncology: advances, challenges, and future directions. J. Clin. Pharmacol. 57, S43–S59. 10.1002/jcph.957 PubMed DOI

Maiti A., Cortes J., Ferrajoli A., Estrov Z., Borthakur G., Garcia-Manero G., et al. . (2017). Homoharringtonine with imatinib in chronic, accelerated, and blast phase chronic myeloid leukemia. Leuk Lymphoma 58, 2240–2242. 10.1080/10428194.2017.1283030 PubMed DOI PMC

Malumbres M., Barbacid M. (2001). To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer 1, 222–231. 10.1038/35106065 PubMed DOI

Malumbres M., Barbacid M. (2009). Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166. 10.1038/nrc2602 PubMed DOI

Malumbres M., Sotillo R., Santamaría D., Galán J., Cerezo A., Ortega S., et al. . (2004). Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504. 10.1016/j.cell.2004.08.002 PubMed DOI

Mandel C. R., Bai Y., Tong L. (2008). Protein factors in pre-mRNA 3'-end processing. Cell. Mol. Life Sci. 65, 1099–1122. 10.1007/s00018-007-7474-3 PubMed DOI PMC

Manzo S. G., Zhou Z.-L., Wang Y.-Q., Marinello J., He J.-X., Li Y.-C., et al. . (2012). Natural product triptolide mediates cancer cell death by triggering CDK7-dependent degradation of RNA polymerase II. Cancer Res. 72, 5363–5373. 10.1158/0008-5472.CAN-12-1006 PubMed DOI

Marin D., Kaeda J. S., Andreasson C., Saunders S. M., Bua M., Olavarria E., et al. . (2005). Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer 103, 1850–1855. 10.1002/cncr.20975 PubMed DOI

Martienssen R., Moazed D. (2015). RNAi and heterochromatin assembly. Cold Spring Harb. Perspect. Biol. 7:a019323. 10.1101/cshperspect.a019323 PubMed DOI PMC

Miller T. W., Balko J. M., Fox E. M., Ghazoui Z., Dunbier A., Anderson H., et al. . (2011). ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1, 338–351. 10.1158/2159-8290.CD-11-0101 PubMed DOI PMC

Moldenhauer G., Salnikov A. V., Lüttgau S., Herr I., Anderl J., Faulstich H. (2012). Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic carcinoma. J. Natl. Cancer Inst. 104, 622–634. 10.1093/jnci/djs140 PubMed DOI

Naing A., Fu S., Zinner R. G., Wheler J. J., Hong D. S., Arakawa K., et al. . (2014). Phase I dose-escalating study of TAS-106 in combination with carboplatin in patients with solid tumors. Invest N. Drugs 32, 154–159. 10.1007/s10637-013-9964-5 PubMed DOI PMC

Nomakuchi T. T., Rigo F., Aznarez I., Krainer A. R. (2016). Antisense oligonucleotide–directed inhibition of nonsense-mediated mRNA decay. Nat. Biotechnol. 34, 164–166. 10.1038/nbt.3427 PubMed DOI PMC

Oettle H., Hilbig A., Seufferlein T., Tsianakas A., Luger T., Schmid R. M., et al. (2011). Phase I/II study with trabedersen (AP 12009) monotherapy for the treatment of patients with advanced pancreatic cancer, malignant melanoma, and colorectal carcinoma. J. Clin. Oncol. 29, 2513–2513. 10.1200/jco.2011.29.15_suppl.2513 DOI

Oliveira A., Beyer G., Chugh R., Skube S. J., Majumder K., Banerjee S., et al. . (2015). Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F. Lab. Invest. 95, 648–659. 10.1038/labinvest.2015.46 PubMed DOI PMC

Ostrem J. M., Peters U., Sos M. L., Wells J. A., Shokat K. M. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551. 10.1038/nature12796 PubMed DOI PMC

Ostrem J. M. L., Shokat K. M. (2016). Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov. 15, 771–785. 10.1038/nrd.2016.139 PubMed DOI

Pahl A., Ko J., Breunig C., Figueroa V., Lehners N., Baumann A., et al. (2018a). HDP-101: preclinical evaluation of a novel anti-BCMA antibody drug conjugates in multiple myeloma. J. Clin. Oncol. 36:e14527 10.1200/JCO.2018.36.15_suppl.e14527 DOI

Pahl A., Lutz C., Hechler T. (2018b). Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov. Today Technol. 30, 85–89. 10.1016/j.ddtec.2018.08.005 PubMed DOI

Palm W., Park Y., Wright K., Pavlova N. N., Tuveson D. A., Thompson C. B. (2015). The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270. 10.1016/j.cell.2015.06.017 PubMed DOI PMC

Pan L., Woodard J. L., Lucas D. M., Fuchs J. R., Kinghorn A. D. (2014). Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. Nat. Prod. Rep. 31, 924–939. 10.1039/c4np00006d PubMed DOI PMC

Pantsar T. (2020). The current understanding of KRAS protein structure and dynamics. Comp. Struct. Biotechnol. J. 18, 189–198. 10.1016/j.csbj.2019.12.004 PubMed DOI PMC

Patel A. B., Greber B. J., Nogales E. (2020). Recent insights into the structure of TFIID, its assembly, and its binding to core promoter. Curr. Opin. Struct. Biol. 61, 17–24. 10.1016/j.sbi.2019.10.001 PubMed DOI PMC

Pecot C. V., Calin G. A., Coleman R. L., Lopez-Berestein G., Sood A. K. (2011). RNA interference in the clinic: challenges and future directions. Nat. Rev. Cancer 11, 59–67. 10.1038/nrc2966 PubMed DOI PMC

Peltonen K., Colis L., Liu H., Jäämaa S., Moore H. M., Enbäck J., et al. . (2010). Identification of Novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents. PLoS ONE 5:e12996. 10.1371/journal.pone.0012996 PubMed DOI PMC

Peltonen K., Colis L., Liu H., Trivedi R., Moubarek M. S., Moore H. M., et al. . (2014). A targeting modality for destruction of RNA polymerase I that possesses anticancer activity. Cancer Cell 25, 77–90. 10.1016/j.ccr.2013.12.009 PubMed DOI PMC

Pereira B., Billaud M., Almeida R. (2017a). RNA-binding proteins in cancer: old players and new actors. Trends Cancer 3, 506–528. 10.1016/j.trecan.2017.05.003 PubMed DOI

Pereira P., Pedro A. Q., Queiroz J. A., Figueiras A. R., Sousa F. (2017b). New insights for therapeutic recombinant human miRNAs heterologous production: Rhodovolum sulfidophilum vs Escherichia coli. Bioengineered 8, 670–677. 10.1080/21655979.2017.1284710 PubMed DOI PMC

Pérez-Salvia M., Esteller M. (2016). Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics 12, 323–339. 10.1080/15592294.2016.1265710 PubMed DOI PMC

Peters T. L., Tillotson J., Yeomans A., Wilmore S. C., Lemm E., Jiménez-Romero C., et al. . (2018). Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo anti-tumor activity. Clin. Cancer Res. 24, 4256–4270. 10.1158/1078-0432.CCR-17-3645 PubMed DOI PMC

Pidala J., Kim J., Jim H., Kharfan-Dabaja M. A., Nishihori T., Fernandez H. F., et al. . (2012). A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica 97, 1882–1889. 10.3324/haematol.2012.067140 PubMed DOI PMC

Plaschka C., Larivière L., Wenzeck L., Seizl M., Hemann M., Tegunov D., et al. . (2015). Architecture of the RNA polymerase II-Mediator core initiation complex. Nature 518, 376–380. 10.1038/nature14229 PubMed DOI

Pon J. R., Marra M. A. (2015). Driver and passenger mutations in cancer. Annu. Rev. Pathol. 10, 25–50. 10.1146/annurev-pathol-012414-040312 PubMed DOI

Poplawski S. G., Garbett K. A., McMahan R. L., Kordasiewicz H. B., Zhao H., Kennedy A. J., et al. . (2020). An antisense oligonucleotide leads to suppressed transcription of Hdac2 and long-term memory enhancement. Mol. Ther. Nucleic. Acids 19, 1399–1412. 10.1016/j.omtn.2020.01.027 PubMed DOI PMC

Prat A., Saura C., Pascual T., Hernando C., Muñoz M., Paré L., et al. . (2020). Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 21, 33–43. 10.1016/S1470-2045(19)30786-7 PubMed DOI

Price D. J., Grove J. R., Calvo V., Avruch J., Bierer B. E. (1992). Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 257, 973–977. 10.1126/science.1380182 PubMed DOI

Proudfoot N. J. (2016). Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science 352:aad9926. 10.1126/science.aad9926 PubMed DOI PMC

Ramot Y., Rotkopf S., Gabai R. M., Zorde Khvalevsky E., Muravnik S., Marzoli G. A., et al. . (2016). Preclinical safety evaluation in rats of a polymeric matrix containing an siRNA drug used as a local and prolonged delivery system for pancreatic cancer therapy. Toxicol Pathol. 44, 856–865. 10.1177/0192623316645860 PubMed DOI

Rangwala R., Chang Y. C., Hu J., Algazy K. M., Evans T. L., Fecher L. A., et al. . (2014). Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10, 1391–1402. 10.4161/auto.29119 PubMed DOI PMC

Rivadeneira D. B., Mayhew C. N., Thangavel C., Sotillo E., Reed C. A., Graña X., et al. . (2010). Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 138, 1920–1930. 10.1053/j.gastro.2010.01.007 PubMed DOI PMC

Robert F., Carrier M., Rawe S., Chen S., Lowe S., Pelletier J. (2009). Altering chemosensitivity by modulating translation elongation. PLoS ONE 4:e5428. 10.1371/journal.pone.0005428 PubMed DOI PMC

Roberti A., Valdes A. F., Torrecillas R., Fraga M. F., Fernandez A. F. (2019). Epigenetics in cancer therapy and nanomedicine. Clin. Epigenetics 11:81. 10.1186/s13148-019-0675-4 PubMed DOI PMC

Rodrigo C. M., Cencic R., Roche S. P., Pelletier J., Porco J. A. (2012). Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies. J. Med. Chem. 55, 558–562. 10.1021/jm201263k PubMed DOI PMC

Rodríguez-Enríquez S., Marín-Hernández Á., Gallardo-Pérez J. C., Pacheco-Velázquez S. C., Belmont-Díaz J. A., Robledo-Cadena D. X., et al. . (2019). Transcriptional regulation of energy metabolism in cancer cells. Cells 8:1225. 10.3390/cells8101225 PubMed DOI PMC

Rodrik-Outmezguine V. S., Okaniwa M., Yao Z., Novotny C. J., McWhirter C., Banaji A., et al. . (2016). Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 534, 272–276. 10.1038/nature17963 PubMed DOI PMC

Roeder R. G. (1996). The role of general initiation factors in transcription by RNA polymerase II. Trends Biochem. Sci. 21, 327–335. 10.1016/S0968-0004(96)10050-5 PubMed DOI

Ross S. J., Revenko A. S., Hanson L. L., Ellston R., Staniszewska A., Whalley N., et al. . (2017). Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci. Trans. Med. 9:eaal5253. 10.1126/scitranslmed.aal5253 PubMed DOI

Rosshandler Y., Shen A. Q., Cortes J., Khoury H. J. (2016). Omacetaxine mepesuccinate for chronic myeloid leukemia. Expert Rev. Hematol. 9, 419–424. 10.1586/17474086.2016.1151351 PubMed DOI

Roux P. P., Topisirovic I. (2018). Signaling pathways involved in the regulation of mRNA translation. Mol. Cell. Biol. 38:e00070-18. 10.1128/MCB.00070-18 PubMed DOI PMC

Rudd M. D., Luse D. S. (1996). Amanitin greatly reduces the rate of transcription by RNA polymerase II ternary complexes but fails to inhibit some transcript cleavage modes. J. Biol. Chem. 271, 21549–21558. 10.1074/jbc.271.35.21549 PubMed DOI

Sabers C. J., Martin M. M., Brunn G. J., Williams J. M., Dumont F. J., Wiederrecht G., et al. . (1995). Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815–822. 10.1074/jbc.270.2.815 PubMed DOI

Sacco A., Federico C., Todoerti K., Ziccheddu B., Giacomini A., Ravelli C., et al. (2019). Specific targeting of KRAS using a novel high-affinity KRAS antisense oligonucleotide in multiple myeloma. Blood 134, 3104–3104. 10.1182/blood-2019-124391 DOI

Schirrmacher V. (2018). From chemotherapy to biological therapy: a review of novel concepts to reduce the side effects of systemic cancer treatment (Review). Int. J. Oncol. 54, 407–419. 10.3892/ijo.2018.4661 PubMed DOI PMC

Schuller A. P., Green R. (2018). Roadblocks and resolutions in eukaryotic translation. Nat. Rev. Mol. Cell Biol. 19, 526–541. 10.1038/s41580-018-0011-4 PubMed DOI PMC

Sehgal S. N. (2003). Sirolimus: its discovery, biological properties, and mechanism of action. Transplant. Proc. 35, 7–14S. 10.1016/s0041-1345(03)00211-2 PubMed DOI

Seifart K. H., Sekeris C. E. (1969). Alpha-amanitin, a specific inhibitor of transcription by mammalian RNA-polymerase. Z. Naturforsch B 24, 1538–1544. 10.1515/znb-1969-1211 PubMed DOI

Senderowicz A. M. (1999). Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 17, 313–320. 10.1023/a:1006353008903 PubMed DOI

Setten R. L., Rossi J. J., Han S. (2019). The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 18, 421–446. 10.1038/s41573-019-0017-4 PubMed DOI

Sharma P., Lioutas A., Fernandez-Fuentes N., Quilez J., Carbonell-Caballero J., Wright R. H. G., et al. . (2019). Arginine citrullination at the C-terminal domain controls RNA polymerase II transcription. Mol. Cell 73, 84–96.e7. 10.1016/j.molcel.2018.10.016 PubMed DOI

Shen S., He X., Yang Z., Zhang L., Liu Y., Zhang Z., et al. . (2018). Discovery of an orally bioavailable dual PI3K/mTOR inhibitor based on sulfonyl-substituted morpholinopyrimidines. ACS Med. Chem. Lett. 9, 719–724. 10.1021/acsmedchemlett.8b00167 PubMed DOI PMC

Shimamoto Y., Koizumi K., Okabe H., Kazuno H., Murakami Y., Nakagawa F., et al. . (2002). Sensitivity of human cancer cells to the new anticancer ribo-nucleoside TAS-106 is correlated with expression of uridine-cytidine kinase 2. Jpn. J. Cancer Res. 93, 825–833. 10.1111/j.1349-7006.2002.tb01325.x PubMed DOI PMC

Simpson E., Dazzi F. (2019). Bone Marrow Transplantation 1957-2019. Front. Immunol. 10:1246. 10.3389/fimmu.2019.01246 PubMed DOI PMC

Singh N. N., Luo D., Singh R. N. (2018). Pre-mRNA splicing modulation by antisense oligonucleotides. Methods Mol. Biol. 1828, 415–437. 10.1007/978-1-4939-8651-4_26 PubMed DOI PMC

Skalniak L., Kocik J., Polak J., Skalniak A., Rak M., Wolnicka-Glubisz A., et al. . (2018). Prolonged idasanutlin (RG7388) treatment leads to the generation of p53-mutated cells. Cancers 10:396. 10.3390/cancers10110396 PubMed DOI PMC

Slack F. J., Chinnaiyan A. M. (2019). The role of non-coding RNAs in oncology. Cell 179, 1033–1055. 10.1016/j.cell.2019.10.017 PubMed DOI PMC

Sledge G. W., Toi M., Neven P., Sohn J., Inoue K., Pivot X., et al. . (2017). MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 35, 2875–2884. 10.1200/JCO.2017.73.7585 PubMed DOI

Smolle M., Workman J. L. (2013). Transcription-associated histone modifications and cryptic transcription. Biochim. Biophys. Acta 1829, 84–97. 10.1016/j.bbagrm.2012.08.008 PubMed DOI PMC

Solassol I., Pinguet F., Quantin X. (2019). FDA- and EMA-approved tyrosine kinase inhibitors in advanced EGFR-mutated non-small cell lung cancer: safety, tolerability, plasma concentration monitoring, and management. Biomolecules 9:668. 10.3390/biom9110668 PubMed DOI PMC

Sonenberg N., Hinnebusch A. G. (2009). Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745. 10.1016/j.cell.2009.01.042 PubMed DOI PMC

Springer A. D., Dowdy S. F. (2018). GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Therap. 28, 109–118. 10.1089/nat.2018.0736 PubMed DOI PMC

Stauder G., Bischof A., Egger T., Hafner M., Herrmuth H., Jachimczak P., et al. (2004). TGF-β2 suppression by the antisense oligonucleotide AP 12009 as treatment for pancreatic cancer: preclinical efficacy data. J. Clin. Oncol. 22, 4106–4106. 10.1200/jco.2004.22.90140.4106 DOI

Stein C. A., Castanotto D. (2017). FDA-approved oligonucleotide therapies in 2017. Mol. Ther. 25, 1069–1075. 10.1016/j.ymthe.2017.03.023 PubMed DOI PMC

Stellrecht C. M., Chen L. S. (2011). Transcription inhibition as a therapeutic target for cancer. Cancers 3, 4170–4190. 10.3390/cancers3044170 PubMed DOI PMC

Stellrecht C. M., Chen L. S., Ayres M. L., Dennison J. B., Shentu S., Chen Y., et al. . (2017). Chlorinated adenosine analogue induces AMPK and autophagy in chronic lymphocytic leukaemia cells during therapy. Br. J. Haematol. 179, 266–271. 10.1111/bjh.14859 PubMed DOI PMC

Su D., Song Y., Li R. (1990). [Comparative clinical study of rheumatoid arthritis treated by triptolide and an ethyl acetate extract of Tripterygium wilfordii]. Zhong Xi Yi Jie He Za Zhi 10, 144–146. PubMed

Tabernero J., Rojo F., Calvo E., Burris H., Judson I., Hazell K., et al. . (2008). Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol. 26, 1603–1610. 10.1200/JCO.2007.14.5482 PubMed DOI

Takahashi R., Prieto-Vila M., Kohama I., Ochiya T. (2019). Development of miRNA-based therapeutic approaches for cancer patients. Cancer Sci. 110, 1140–1147. 10.1111/cas.13965 PubMed DOI PMC

Tang W., Zhao G. (2019). Small molecules targeting HIF-1α pathway for cancer therapy in recent years. Bioorg. Med. Chem. 28:115235. 10.1016/j.bmc.2019.115235 PubMed DOI

Thangavel C., Dean J. L., Ertel A., Knudsen K. E., Aldaz C. M., Witkiewicz A. K., et al. . (2011). Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer 18, 333–345. 10.1530/ERC-10-0262 PubMed DOI PMC

Thoreen C. C., Kang S. A., Chang J. W., Liu Q., Zhang J., Gao Y., et al. . (2009). An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032. 10.1074/jbc.M900301200 PubMed DOI PMC

Tian T., Li X., Zhang J. (2019). mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int. J. Mol. Sci. 20:755. 10.3390/ijms20030755 PubMed DOI PMC

Titov D. V., Gilman B., He Q.-L., Bhat S., Low W.-K., Dang Y., et al. . (2011). XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat. Chem. Biol. 7, 182–188. 10.1038/nchembio.522 PubMed DOI PMC

Toogood P. L., Harvey P. J., Repine J. T., Sheehan D. J., VanderWel S. N., Zhou H., et al. . (2005). Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem. 48, 2388–2406. 10.1021/jm049354h PubMed DOI

Traut T. W. (1994). Physiological concentrations of purines and pyrimidines. Mol. Cell Biochem. 140, 1–22. 10.1007/BF00928361 PubMed DOI

Tsao A., Hui E. P., Juergens R., Marur S., Huat T. E., Cher G. B., et al. . (2013). Phase II study of TAS-106 in patients with platinum-failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer. Cancer Med. 2, 351–359. 10.1002/cam4.79 PubMed DOI PMC

Tu M.-J., Ho P. Y., Zhang Q.-Y., Jian C., Qiu J.-X., Kim E. J., et al. . (2019). Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models. Cancer Lett. 442, 82–90. 10.1016/j.canlet.2018.10.038 PubMed DOI PMC

Turner N. C., Ro J., Andr,é F., Loi S., Verma S., Iwata H., et al. . (2015). Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219. 10.1056/NEJMoa1505270 PubMed DOI

Van Roosbroeck K., Calin G. A. (2017). Cancer hallmarks and MicroRNAs: the therapeutic connection. Adv. Cancer Res. 135, 119–149. 10.1016/bs.acr.2017.06.002 PubMed DOI

VanderWel S. N., Harvey P. J., McNamara D. J., Repine J. T., Keller P. R., Quin J., et al. . (2005). Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4. J. Med. Chem. 48, 2371–2387. 10.1021/jm049355+ PubMed DOI

Vézina C., Kudelski A., Sehgal S. N. (1975). Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726. 10.7164/antibiotics.28.721 PubMed DOI

Villicaña C., Cruz G., Zurita M. (2014). The basal transcription machinery as a target for cancer therapy. Cancer Cell Int. 14:18. 10.1186/1475-2867-14-18 PubMed DOI PMC

Vispé S., DeVries L., Créancier L., Besse J., Bréand S., Hobson D. J., et al. . (2009). Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol. Cancer Ther. 8, 2780–2790. 10.1158/1535-7163.MCT-09-0549 PubMed DOI

Vogel C., Marcotte E. M. (2012). Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227–232. 10.1038/nrg3185 PubMed DOI PMC

Wagner M. J., Mitra R., McArthur M. J., Baze W., Barnhart K., Wu S., et al. . (2017). Preclinical mammalian safety studies of EPHARNA (DOPC nanoliposomal EphA2-targeted siRNA). Mol Cancer Ther. 16, 1114–1123. 10.1158/1535-7163.MCT-16-0541 PubMed DOI PMC

Wang P.-F., Qiu H.-Y., Zhu H.-L. (2019). A patent review of BRAF inhibitors: 2013-2018. Expert Opin. Ther. Pat. 29, 595–603. 10.1080/13543776.2019.1640680 PubMed DOI

Wang W.-P., Ho P. Y., Chen Q.-X., Addepalli B., Limbach P. A., Li M.-M., et al. . (2015). Bioengineering novel chimeric microRNA-34a for prodrug cancer therapy: high-yield expression and purification, and structural and functional characterization. J. Pharmacol. Exp. Ther. 354, 131–141. 10.1124/jpet.115.225631 PubMed DOI PMC

Wang Z., Jin H., Xu R., Mei Q., Fan D. (2009). Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp. Mol. Med. 41, 717–727. 10.3858/emm.2009.41.10.078 PubMed DOI PMC

Ward A. J., Norrbom M., Chun S., Bennett C. F., Rigo F. (2014). Nonsense-mediated decay as a terminating mechanism for antisense oligonucleotides. Nucleic Acids Res. 42, 5871–5879. 10.1093/nar/gku184 PubMed DOI PMC

Waring M. J., Chen H., Rabow A. A., Walker G., Bobby R., Boiko S., et al. . (2016). Potent and selective bivalent inhibitors of BET bromodomains. Nat. Chem. Biol. 12, 1097–1104. 10.1038/nchembio.2210 PubMed DOI

Watson J., Baker T., Bell S., Gann A., Levine M., Losick R. (2013). Part 5: regulation, in Molecular Biology of the Gene, ed Wilbur B. (New York, NY: Pearson; ), 609–792.

Wei T., Najmi S. M., Liu H., Peltonen K., Kucerova A., Schneider D. A., et al. . (2018). Small-molecule targeting of RNA polymerase I activates a conserved transcription elongation checkpoint. Cell Rep. 23, 404–414. 10.1016/j.celrep.2018.03.066 PubMed DOI PMC

Wetzler M., Segal D. (2011). Omacetaxine as an anticancer therapeutic: what is old is new again. Curr. Pharm. Des. 17, 59–64. 10.2174/138161211795049778 PubMed DOI

Whelan J. (2005). First clinical data on RNAi. Drug Discov. Today 10, 1014–1015. 10.1016/S1359-6446(05)03547-6 PubMed DOI

Wiederrecht G. J., Sabers C. J., Brunn G. J., Martin M. M., Dumont F. J., Abraham R. T. (1995). Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells. Prog. Cell Cycle Res. 1, 53–71. 10.1007/978-1-4615-1809-9_5 PubMed DOI

Wilting R. H., Dannenberg J.-H. (2012). Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist. Update 15, 21–38. 10.1016/j.drup.2012.01.008 PubMed DOI

Wolfe A. L., Singh K., Zhong Y., Drewe P., Rajasekhar V. K., Sanghvi V. R., et al. . (2014). RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70. 10.1038/nature13485 PubMed DOI PMC

Xie J., Wang X., Proud C. G. (2016). mTOR inhibitors in cancer therapy. F1000Res 5:2078. 10.12688/f1000research.9207.1 PubMed DOI PMC

Xue J. Y., Zhao Y., Aronowitz J., Mai T. T., Vides A., Qeriqi B., et al. . (2020). Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577, 421–425. 10.1038/s41586-019-1884-x PubMed DOI PMC

Yamakawa K., Nakano-Narusawa Y., Hashimoto N., Yokohira M., Matsuda Y. (2019). Development and clinical trials of nucleic acid medicines for pancreatic cancer treatment. Int. J. Mol. Sci. 20:4224. 10.3390/ijms20174224 PubMed DOI PMC

Yang H., Liang S.-Q., Schmid R. A., Peng R.-W. (2019). New horizons in KRAS-mutant lung cancer: dawn after darkness. Front. Oncol. 9:953. 10.3389/fonc.2019.00953 PubMed DOI PMC

Yin W., Rogge M. (2019). Targeting RNA: a transformative therapeutic strategy. Clin. Transl. Sci. 12, 98–112. 10.1111/cts.12624 PubMed DOI PMC

Yu A.-M., Jian C., Yu A. H., Tu M.-J. (2019). RNA therapy: are we using the right molecules? Pharmacol. Therap. 196, 91–104. 10.1016/j.pharmthera.2018.11.011 PubMed DOI PMC

Yu T., Li N., Wu C., Guan A., Li Y., Peng Z., et al. . (2018). Discovery of pyridopyrimidinones as potent and orally active dual inhibitors of PI3K/mTOR. ACS Med. Chem. Lett. 9, 256–261. 10.1021/acsmedchemlett.8b00002 PubMed DOI PMC

Zeidner J. F., Karp J. E. (2015). Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk. Res. 39, 1312–1318. 10.1016/j.leukres.2015.10.010 PubMed DOI

Zhang L., Liao Y., Tang L. (2019a). MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. J. Exp. Clin. Cancer Res. 38:53. 10.1186/s13046-019-1059-5 PubMed DOI PMC

Zhang Q.-W., Ye Z.-D., Shi L. (2019b). c-Met kinase inhibitors: an update patent review (2014-2017). Exp. Opin. Ther. Pat. 29, 25–41. 10.1080/13543776.2019.1552261 PubMed DOI

Zhang Q.-Y., Ho P. Y., Tu M.-J., Jilek J. L., Chen Q.-X., Zeng S., et al. . (2018). Lipidation of polyethylenimine-based polyplex increases serum stability of bioengineered RNAi agents and offers more consistent tumoral gene knockdown in vivo. Int. J. Pharm. 547, 537–544. 10.1016/j.ijpharm.2018.06.026 PubMed DOI PMC

Zhao H., Chen G., Liang H. (2019). Dual PI3K/mTOR Inhibitor, XL765, suppresses glioblastoma growth by inducing ER stress-dependent apoptosis. Oncol. Targets Ther. 12, 5415–5424. 10.2147/OTT.S210128 PubMed DOI PMC

Zhao Y., Tu M.-J., Wang W.-P., Qiu J.-X., Yu A.-X., Yu A.-M. (2016). Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. Sci. Rep. 6, 1–11. 10.1038/srep26611 PubMed DOI PMC

Zhao Y., Tu M.-J., Yu Y.-F., Wang W.-P., Chen Q.-X., Qiu J.-X., et al. . (2015). Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth. Biochem. Pharmacol. 98, 602–613. 10.1016/j.bcp.2015.10.015 PubMed DOI PMC

Zhao Z., Shilatifard A. (2019). Epigenetic modifications of histones in cancer. Genome Biol. 20:245. 10.1186/s13059-019-1870-5 PubMed DOI PMC

Zhong M., Lee G. M., Sijbesma E., Ottmann C., Arkin M. R. (2019). Modulating protein-protein interaction networks in protein homeostasis. Curr. Opin. Chem. Biol. 50, 55–65. 10.1016/j.cbpa.2019.02.012 PubMed DOI PMC

Zhou J., Rossi J. (2017). Aptamers as targeted therapeutics: current potential and challenges. Nat. Rev. Drug Discov. 16, 181–202. 10.1038/nrd.2016.199 PubMed DOI PMC

Zuckerman J. E., Davis M. E. (2015). Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat. Rev. Drug Discov. 14, 843–856. 10.1038/nrd4685 PubMed DOI

Heterogeneous protein dynamics links to mitochondrial activity, glucose transporter, and ALDH cancer stem cell properties